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Synthesis method of (R)-moprolol

A synthesis method and a technology of the equation, applied in the synthesis field of moprol, can solve the problems of need, not suitable for industrial application, expensive reagents, etc., and achieve the effects of simple operation, good industrial application prospect and short cycle.

Inactive Publication Date: 2014-06-18
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires stoichiometric chiral reagents, which are expensive and not suitable for industrial applications

Method used

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  • Synthesis method of (R)-moprolol
  • Synthesis method of (R)-moprolol
  • Synthesis method of (R)-moprolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the preparation of (R)-moprorol [compound 3 or formula (I)]

[0033] (1) Preparation of compound 1 or formula (III) [(R)-3-o-methoxyphenoxy-1,2-propanediol]

[0034] Dissolve guaiacol (29.8, 0.24mol) in 240mL of absolute ethanol, add sodium hydroxide (10.7g, 0.27mol) in batches at room temperature, then add phase transfer catalyst tetrabutylammonium bromide (0.32g, 1.0mmol), add (R)-3-chloro-1,2-propanediol (23.3g, 0.21mol) dropwise, after dropping, react at 70-73°C for 5 hours, after the reaction is completed, filter while hot, and concentrate the filtrate under reduced pressure, Petroleum ether was recrystallized to obtain 33.2 g of white solid (R)-guaifenesin, with a yield of 80.1%. The experimental data are as follows:

[0035] mp 97-99°C, [α] D 20 = -9.5 (c 1.0, MeOH); 1 HNMR (400MHZ, CDCl 3 ): δ3.77-3.83 (m, 2H, CH 2 ), 3.86(s, 3H, CH 3 ), 4.06-4.09 (m, 2H, CH 2 ), 4.16-4.20 (m, 1H, CH), 6.89-7.01 (m, 4H, Ar).; IR (KBr) cm -1 : 3242, 2941, 2...

Embodiment 2

[0043] (1) Preparation of compound 1 or formula (III) [(R)-3-o-methoxyphenoxy-1,2-propanediol]

[0044] Guaiacol (14.9g, 0.12mol) was dissolved in 120mL of anhydrous methanol, sodium hydroxide (8.0g, 0.2mol) was added in batches at room temperature, and then a phase transfer catalyst benzyltriethylammonium chloride (benzyltriethylammonium) was added ( 0.24g, 1.0mmol), drop (R)-3-chloro-1,2-propanediol (23.3g, 0.21mol), dropwise, 55 ~ 60 ℃ for 8 hours, the reaction is complete, filtered while hot, the filtrate reduced Concentrated under reduced pressure, recrystallized from toluene to obtain 19.2 g of white solid (R)-guaifenesin, yield 81.6%, mp97-99°C, [α] D 20 = -9.4 (c 1.0, MeOH)

[0045] (2) Preparation of compound 2 or formula (IV) [(S)-4-o-methoxyphenoxymethyl-1,3,2-dioxathiolane-2-oxide]

[0046] Compound 1 (9.9 g, 0.05 mol) was dissolved in 100 mL of dichloromethane, and a mixed solution of thionyl chloride (6.5 g, 0.055 mol) and 10 mL of dichloromethane was added dr...

Embodiment 3

[0050] (1) Preparation of compound 1 or formula (III) [(R)-3-o-methoxyphenoxy-1,2-propanediol]

[0051] Dissolve guaiacol (12.4g, 0.1mol) in 240mL isopropanol, add sodium hydroxide (6.0g, 0.15mol) in batches at room temperature, then add phase transfer catalyst tetrabutylammonium bromide (0.16g , 0.5mmol), dropwise added (R)-3-chloro-1,2-propanediol (44.3g, 0.4mol), after dropping, reacted at 80-85°C for 4 hours, after the reaction was completed, filtered while hot, and concentrated the filtrate under reduced pressure , recrystallized from cyclohexane to obtain 17.3 g of white solid (R)-guaifenesin, yield 87.3%, mp97-99°C, [α] D 20 = -9.4 (c 1.0, MeOH)

[0052] (2) Preparation of compound 2 or formula (IV) [(S)-4-o-methoxyphenoxymethyl-1,3,2-dioxathiolane-2-oxide]

[0053] Compound 1 (10.0 g, 0.05 mol) was dissolved in 100 mL of dichloromethane, and a mixed solution of thionyl chloride (6.5 g, 0.055 mol) and 10 mL of dichloromethane was added dropwise at a temperature contr...

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Abstract

The invention discloses a synthesis method of (R)-moprolol, which comprises the following steps: taking (R)-3-chlorine-1, 2-propanediol with high optical purity as raw material, and undergoing hydrolysis, condensation with guaiacol, cyclization of thionyl chloride, and open-cycle of isopropamide to obtain (R)-moprolol with high enantiomeric purity. The synthesis method has the advantage of low cost and easy taking of raw material, simple operation, temperate condition, short period, high yield and optical purity of the product, and better industrialized application prospect.

Description

technical field [0001] The invention relates to a method for synthesizing organic matter, in particular to a method for synthesizing (R)-moprorol. Background technique [0002] Moprolol (Moprolol), also known as methotrexate, chemical name 1-isopropylamine-3-o-methoxyphenoxy-2-propanol, is a representative of β-receptor blockers drug. β-receptor blockers are a class of drugs developed in the 1960s to treat cardiovascular diseases. They have shown good effects in fighting angina pectoris, arrhythmia and hypertension, and their importance has been recognized by the global medical community. It has become one of the basic medicines for the treatment of cardiovascular diseases. It is particularly effective against heart failure and myocardial infarction, and is an important means for the current treatment of chronic heart failure and myocardial infarction. [0003] At present, the drug is mainly supplied in the form of racemate in clinical practice, and pharmacological studie...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/34C07C213/02A61P9/10A61P9/12A61P9/06
Inventor 王朝阳陈小丽朱锦桃王燕愈开新孙斌李忠雷
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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